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1
Department of Radiology, Kyoto University Graduate School of Medicine, 54
Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, Japan, 606-8507.
2
Department of Radiology, Kyoto University Hospital, Kyoto, Japan,
606-8507.
3
Department of Transplantation Immunology and Transplant Surgery, Kyoto
University Graduate School of Medicine, Kyoto, Japan, 606-8507.
4
Organ Transplantation Unit, Kyoto University Hospital, Kyoto, Japan,
606-8507.
5
Laboratory of Pathology, Kyoto Katsura Hospital, 17 Yamada Hirao-cho,
Nishikyo-ku, Kyoto, Japan.
6
Department of Medicine and Clinical Science, Kyoto University Hospital, Kyoto,
Japan, 606-8507.
Address correspondence to Y. Maetani.
Abstract
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MATERIALS AND METHODS. Imaging findings of 59 benign hepatic nodules in four patients with chronic Budd-Chiari syndrome were analyzed retrospectively, and radiologic— pathologic correlation was performed in three patients with 50 hepatic nodules who underwent liver transplantation. All patients underwent multiphasic helical CT. In three patients with 29 lesions, MR imaging, including a multiphasic dynamic study, was performed. The CT and MR imaging findings in these patients were compared with those of 103 small hepatocellular carcinomas in 56 other patients (54 of them displayed chronic hepatitis or liver cirrhosis associated with viral hepatitis but none had Budd-Chiari syndrome). Image analysis was performed by two radiologists with no knowledge of the diagnosis.
RESULTS. All patients with Budd-Chiari syndrome exhibited multiple benign nodules up to 3 cm in diameter, and 42 of 59 lesions were hypervascular. Microscopically, 15 of 32 nodules demonstrated a central scar; moreover, some nodules closely resembled focal nodular hyperplasia. Frequencies of hyperintensity on T1-weighted images (14/29 vs 25/103), hypointensity on T2-weighted images (7/29 vs 1/103), and the presence of a central scar (6/59 vs 1/103) were significantly higher in benign nodules than in hepatocellular carcinomas (p < 0.05; Fisher's exact test). Moreover, for lesions larger than 1 cm, imaging studies revealed a central scar in six of 15 benign lesions.
CONCLUSION. Benign hepatic nodules in patients with in Budd-Chiari syndrome are usually small, multiple, and hypervascular. The presence of a central scar is a characteristic feature in those larger than 1 cm in diameter.
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In patients with chronic Budd-Chiari syndrome, hepatocellular carcinoma also can develop [10, 11], and it is important to distinguish benign hepatic nodules from hepatocellular carcinoma because treatment differs radically. On radiologic examination, both benign nodules and hepatocellular carcinoma have been reported as hypervascular [6]. On the other hand, benign nodules composed of fairly normal hepatocytes often have a central scar and resemble focal nodular hyperplasia pathologically [7,8,9]. Therefore, the presence of a central scar may suggest benignity. However, to our knowledge, no radiologic study has documented the presence of a central scar of benign lesions in Budd-Chiari syndrome. In addition, the incidence of central scars in hepatocellular carcinoma remains unclear. The purpose of our investigation was to describe the imaging appearance of benign hepatic nodules in Budd-Chiari syndrome and to compare it with that of hepatocellular carcinoma, emphasizing the presence of a central scar.
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Two patients were treated with balloon angioplasty of the inferior vena
cava and hepatic veins in other hospitals. Additionally, one of these
participants had been treated with transjugular intrahepatic portosystemic
shunt with stent placement. However, they did not respond to these treatments.
The other two patients were diagnosed with liver cirrhosis of unknown cause at
other hospitals. These four patients were referred to our hospital for
possible liver transplantation. Subsequently, three individuals underwent
transplantation. The interval between initial diagnosis of Budd-Chiari
syndrome and liver transplantation in these patients was 3 years, 7 years, and
7 months. The remaining patient was treated with balloon angioplasty of the
right hepatic vein with stent placement. In this case, sonography failed to
detect hepatic nodules, and no histopathologic specimen of the lesion was
obtained. However, hepatic nodules were diagnosed as benign in this patient
based on no change in the imaging appearance for more than 1 year and blood
-fetoprotein levels of less than 10 ng/mL. None of these patients
displayed positive markers for viral hepatitis.
We also attempted to review radiologic findings of small hepatocellular carcinoma. From December 1997 to July 1999, 56 consecutive patients presenting with hepatocellular carcinomas smaller than 3 cm in diameter who had undergone both CT and MR imaging were included in the analysis. These patients included 36 males and 20 females, ranging in age from 16 to 83 years (mean age, 66 years). All but two patients displayed chronic hepatitis or liver cirrhosis associated with viral hepatitis (hepatitis B in 13, hepatitis C in 38, and both in three patients). A total of 103 hepatocellular carcinomas smaller than 3 cm (0.2-3 cm; mean diameter, 1.4 cm) were observed. Twenty-four patients exhibited a single lesion, and 32 patients had multiple hepatocellular carcinomas. Of these 32 patients, seven had more than five tumors; however, a large hepatocellular carcinoma in excess of 5 cm was present in all of them.
Diagnosis of hepatocellular carcinoma was confirmed by surgical biopsy in
37 nodules in 31 patients. For 63 lesions in 23 patients, the following
criteria were used: hypervascularity revealed on any radiologic modality,
iodized oil accumulation after trans-catheter arterial embolization therapy,
or both; and elevated blood -fetoprotein level that dropped immediately
after transcatheter arterial embolization. In the case of the remaining three
nodules in two patients with liver cirrhosis, diagnoses of the lesions as
hepatocellular carcinomas were based on lesion enlargement in the imaging
appearance as well as an increase of blood -fetoprotein levels during
follow-up.
Imaging
CT was performed in all four patients with Budd-Chiari syndrome; three of
these patients also underwent MR imaging. Hepatic angiography was performed in
two patients. Another patient underwent hepatic angiography at an outside
hospital, and these images were also available for review. All radiologic
studies were performed within 1 month before surgery in the three patients
with Budd-Chiari syndrome who underwent liver transplantation. All 56 subjects
with hepatocellular carcinoma underwent CT and MR examinations and hepatic
angiography was performed in 49 of these patients.
Helical CT studies were conducted with two units (HiSpeed Advantage, General Electric Medical Systems, Milwaukee, WI; CT-W3000, Hitachi Medical Systems, Tokyo, Japan). Scanning parameters were 120 kV, 200 mA, collimation of 7 mm, and table speed of 10 mL/sec with reconstruction increments of 7 mm. Unenhanced scans as well as dualphase contrast-enhanced images were acquired in all patients. Scanning delay for early and late phase imaging was 30 sec and 120 sec, respectively, after initiation of power injection of 100 mL nonionic contrast material (Iopamiron 370, Nihon Schering, Osaka, Japan; or Omnipaque 350, Daiichi Pharmaceutical, Tokyo, Japan) at a rate of 3 mL/sec.
MR imaging was performed on a 1.5-T superconducting unit (Signa Horizon; General Electric Medical Systems) in all patients. All MR images were obtained in the axial plane with a phased array multicoil for the body. T2-weighted images were obtained with respiratory-triggered fast spin-echo sequences. T1-weighted gradient-echo images were obtained using fast multiplanar spoiled gradient-recalled imaging in the steady state and both in-phase, and opposed-phase images were obtained. Then, multiphasic contrast-enhanced dynamic gradient-echo images were also obtained. After the unenhanced images were acquired, a bolus of 0.1 mmol/kg of gadodiamide (Omniscan; Daiichi Pharmaceutical) was injected at a rate of 2 mL/sec followed by a 20 mL flush of normal saline via a power injector. The scan delay for triphasic dynamic imaging was 20, 80, and 180 sec after initiation of contrast injection. In one patient with Budd-Chiari syndrome, T1-weighted spin-echo images were obtained before and 5 min after injection of contrast material. In principle, the chemical shift selective fat-suppression technique was used for T2-weighted images and multiphasic contrast-enhanced dynamic gradient-echo images.
For hepatic angiography, both right and left hepatic angiograms were obtained in addition to a celiac angiogram for all patients, including one patient with Budd-Chiari syndrome who underwent angiography at an outside hospital. In one patient with Budd-Chiari syndrome, both CT hepatic arteriography and CT during arterial portography were also performed.
In four patients with Budd-Chiari syndrome, sonography was performed with a Power Vison 8000 (Toshiba Medical, Tokyo, Japan) or a SONOLINE Elegra (Siemens Asahi Medics, Tokyo, Japan) using a 3.5-MHz convex probe. Reports of these sonographic findings were also available for review.
Image Analyses
Images of hepatic nodules in Budd-Chiari syndrome and hepatocellular
carcinomas were retrospectively evaluated in conference by two radiologists
with no knowledge of the diagnosis of hepatic lesions or underlying liver
disease. All CT and MR imaging sequences were evaluated during the same review
session. The radiologists reached a consensus regarding the following
features: number; size; attenuation at unenhanced CT; signal intensity at MR
imaging; lesion vascularization at contrast-enhanced CT, MR imaging,
angiography, and CT hepatic arteriography; and presence of a central scar at
CT and MR imaging. Differences between these imaging findings of benign
hepatic nodules in Budd-Chiari syndrome and those of small hepatocellular
carcinomas were analyzed statistically using Fisher's exact test. A two-tailed
p value of less than 0.05 was considered significant.
Pathologic Review
The explanted livers in three patients with Budd-Chiari syndrome were
serially sectioned at intervals of 5 mm (n = 1) or 10 mm (n
= 2). All visible nodules larger than 3 mm in diameter were recorded, and
nodules larger than 5 mm in diameter were examined microscopically. Two
pathologists with no knowledge of the radiologic findings reviewed the
histologic specimens retrospectively. The lesions were classified according to
the guidelines of the International Working Party
[12]. Subsequently, one of the
pathologists and a radiologist worked in conference to compare, on a
one-by-one basis, all nodular lesions revealed on radiologic examination with
corresponding nodules in the explanted liver specimens in terms of location,
size, number, and the presence of a central scar.
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Imaging Features of Hepatic Nodules in Budd-Chiari Syndrome
In addition to 50 nodules larger than 3 mm in diameter in the three
individuals receiving transplantation, nine nodules were found with
combinations of all imaging procedures in the remaining patient. Thus, at
least 59 hepatic nodules up to 3 cm in diameter were detected in these four
patients. No nodules were detected with sonography probably because of coarse
liver parenchyma.
Of 59 lesions, three nodules were detected on unenhanced CT, 21 on early phase dynamic CT, and nine on late phase dynamic CT (Table 1). Unenhanced CT scans showed heterogeneous liver parenchyma with patchy areas of hypodensity (attenuation, 42 ± 5 H) compared with the attenuation value of the spleen. However, the attenuation values of three lesions disclosed on unenhanced CT were 46, 47, and 65 H, and they were hyperattenuating compared with surrounding liver parenchyma (Fig. 2A).
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MR imaging was performed in three patients with 29 benign hepatic nodules; these findings are summarized in Table 2. Of the 29 nodules, seven lesions were discovered on T2-weighted images. All of them were larger than 1 cm in diameter and hypointense compared with the surrounding liver (Figs. 2B and 3A). Fourteen lesions, including five nodules smaller than 1 cm, could be identified on T1-weighted gradient-echo images: eight on arterial dominant phase and 11 on delayed contrast-enhanced MR studies. All nodules identified on T1-weighted gradient-echo images were hyperintense compared with the surrounding liver (Figs. 2C and 3B); no lesions showed signal loss on in-phase and opposed-phase T1-weighted gradient-echo images.
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Among 59 lesions, 42 nodules displayed hypervascularity in at least one imaging modality. Most nodules larger than 1 cm in diameter were hypervascular at any imaging modality. For smaller lesions, however, dynamic CT and MR imaging often failed to reveal hypervascularity (Tables 1 and 2) that was identified on angiography or CT hepatic arteriography (Figs. 4A and 4C). In a single patient, the vascular supply to the lesion arose centrally and radiated peripherally on angiography (Fig. 3D)—a finding similar to a spoke wheel pattern characteristic of focal nodular hyperplasia.
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In one patient, CT during arterial portography revealed heterogeneous hepatic enhancement that consisted of multiple focal patchy enhancements. The portal venules ran in the center of these patchy enhancement areas (Fig. 4B). All hypervascular small nodules disclosed on CT hepatic arteriography were located at poorly enhanced areas on CT during arterial portography (Fig. 4C).
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Of 15 lesions larger than 1 cm in diameter, a central scar was found with either CT or MR imaging in six nodules. Radiologic examination revealed a central scar in five of eight nodules larger than 1 cm in which the presence of a central scar was confirmed pathologically. On CT, a central scar was shown as a central hypoattenuating area on unenhanced scanning (Fig 2A) or at early phase of contrast-enhanced dynamic scanning. On MR imaging, a central scar was shown as a central hypointensity area on T1-weighted images (Figs. 2C and 3B) and as a central hyperintensity area on T2-weighted images (Figs. 2B and 3A). In the delayed phase of contrast-enhanced imaging, the central scar showed high signal intensity (Fig. 3C). Neither CT nor MR imaging could detect a central scar for lesions smaller than 1 cm in diameter in any patient.
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Imaging Features of Small Hepatocellular Carcinoma
Of the 103 small hepatocellular carcinomas, lesion signal intensity on
T1-weighted MR images was high in 25 tumors and low in 23 tumors. On
T2-weighted images, 41 lesions showed hyperintensity, whereas only one
hypovascular tumor revealed hypointensity. That lesion was diagnosed as
well-differentiated hepatocellular carcinoma on pathologic examination. Two
lesions that were hyperattenuating compared with the surrounding liver
parenchyma were revealed on unenhanced CT. Nearly all lesions were homogeneous
on unenhanced CT and T1- and T2-weighted MR imaging. A central scar was
evident in only one tumor.
The comparison of various imaging findings between benign hepatic nodules in Budd-Chiari syndrome and small hepatocellular carcinomas is summarized in Table 3. The frequencies of hyperintensity on T1-weighted images, hypointensity on T2-weighted images, and the presence of a central scar were significantly higher in benign hepatic nodules in Budd-Chiari syndrome than in small hepatocellular carcinomas.
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In general, the pathogenesis of benign hepatic nodules in Budd-Chiari syndrome remains unclear. Some researchers have suggested that the disturbance of hepatic microcirculation associated with obstruction of the hepatic vein and the elevation of hepatocellular growth factors may play important roles [3, 6, 8]. Vilgrain et al. [6] speculated that the cause of benign hepatic nodules may be portacaval anastomosis. In their study, surgical portacaval anastomosis was created in 16 of 19 patients exhibiting benign hepatic nodules. It has been reported that numerous nodules and multiple arteries within the portal triads developed in rats with surgical portacaval shunts [13, 14]. In contrast, Tanaka and Wanless [8] surmised that portal vein thrombosis was responsible for lesion growth. They found that portal vein thrombosis occurred frequently in Budd-Chiari syndrome and that regenerative nodules developed in regions with portal vein thrombosis and relatively good hepatic vein drainage. The point in common shared by these two hypotheses is the decrease of portal venous flow. Additionally, our study clarified that these nodules arose in areas where portal venous flow decreased on CT during arterial portography, and we hypothesize that the decrease of portal venous flow is closely related to the cause of the nodules.
On pathologic examination, Wanless [7] reported that nodules between 5 and 40 mm in diameter were apparent in eight of 10 livers in patients with Budd-Chiari syndrome. Moreover, Tanaka and Wanless [8] found nodules of at least 5 mm diameter in nine of 15 livers in patients with Budd-Chiari syndrome. Despite this fact, radiologic data for these nodules are scarce. It is probable that a considerable number of these nodules have been overlooked [3]. Although nodules are typically multiple, they are small, ranging from a few millimeters to 4 cm [2,3,4, 7, 9]. To detect these lesions, it is important to perform arterial phase of dynamic CT or MR imaging, because they are usually hypervascular [3, 5, 6, 15]. We think that the frequency of benign hepatic nodules revealed by imaging has been increasing as a result of improved imaging techniques and routine use of multiphasic contrast-enhanced CT and MR imaging. Vilgrain et al. [6] found benign hepatic nodules were in 19 of 77 patients with Budd-Chiari syndrome by using various imaging techniques.
In our investigation, all nodules detected on unenhanced CT were
hyperattenuating compared with the surrounding liver. Vilgrain et al.
[6] also documented that the
lesions were hyperattenuating in eight of 13 patients. However, the condition
of the liver parenchyma must be considered in Budd-Chiari syndrome: unenhanced
CT revealed intrahepatic hypodense areas that could be related to congestion,
hemorrhagic necrosis, or fibrosis
[16,
17]. On the contrary, our
study showed congestion was usually absent within the nodules, despite
extranodular parenchymal congestion. We surmise that the nodule appears to be
hyperattenuating partly as a result of surrounding hypodense liver
parenchyma.
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Lesion signal intensity on T2-weighted MR imaging is variable. Soyer et al. [2] showed isointense or hyperintense nodules, whereas Rha et al. [5] found that lesions were isointense to slightly hypointense. Vilgrain et al. [6] documented hyperintense nodules in nine of 15 patients and hypointense nodules in three patients. Our study revealed that more than two thirds of nodules were invisible (or isointense) and that all lesions that could be detected on T2-weighted images were hypointense. It has been reported that liver parenchyma with congestion and necrosis revealed hyperintensity on T2-weighted images [18]. We hypothesize that this observation may partially account for lesion hypointensity on T2-weighted images. On the other hand, most lesions displayed hyperintensity on T1-weighted images [2, 5, 6]. Our investigation showed that all nodules detected on T1-weighted images exhibited hyperintensity that was not suppressed on in-phase and opposed-phase imaging. Pathologically, fatty degeneration was observed in only two lesions. The reason for this hyperintensity remains unclear, although it might be caused in part by the lower signal intensity of the congested perinodular area.
Wanless [7] and Tanaka and Wanless [8] emphasized that benign hepatic nodules in Budd-Chiari syndrome often closely resembled focal nodular hyperplasia grossly and microscopically. Zhou et al. [9] also reported that large nodules with a central scar were very similar to focal nodular hyperplasia pathologically. In our study, a central scar was often observed in nodules larger than 1 cm in diameter on imaging as well as on pathologic examination. We believe that the presence of a central scar is a characteristic finding of benign hepatic nodules larger than 1 cm in Budd-Chiari syndrome. To our knowledge, no radiologic study has documented the presence of a central scar in these lesions. However, Vilgrain et al. [6] observed a peripheral rim in the largest nodule in two patients. Soyer et al. [2] also found that one lesion, which was hyperintense on T2-weighted images, displayed a hypointense rim. We surmise that these findings may reflect the presence of a large central scar.
In chronic Budd-Chiari syndrome, persistent hepatic outflow obstruction results in hepatocyte death, fibrosis, and cirrhosis [9], and hepatocellular carcinoma also can develop [10, 11]. In our study, no patients with Budd-Chiari syndrome exhibited hepatocellular carcinoma. However, small hepatocellular carcinomas measuring less than 3 cm in diameter are often found in our patients. As a result, we reviewed radiologic findings of small hepatocellular carcinoma and compared them with findings of benign hepatic nodules in Budd-Chiari syndrome.
Vilgrain et al. [6] suggested that the hyperattenuation of nodules on unenhanced CT might be suggestive of benignity, because they found that benign nodules showed hyperattenuation in eight of 13 patients, whereas no hepatocellular carcinoma exhibited hyperattenuation. In our study, however, the frequencies of hyperattenuating lesions of benign hepatic nodules and those of hepatocellular carcinomas did not differ significantly.
Hyperintensity on T1-weighted MR images has been reported in benign hepatic nodules in Budd-Chiari syndrome [2, 5, 6] as well as in hepatocellular carcinoma [19]. Although our study showed that benign hepatic nodules revealed hyperintensity on T1-weighted images more often than did small hepatocellular carcinomas, the distinction between these lesions may be difficult to make on the basis of signal intensity on T1-weighted MR imaging alone.
In the cirrhotic liver, hypointensity of focal lesions on T2-weighted image suggests a diagnosis of adenomatous hyperplastic nodules [20], which are usually hypovascular [21]. In our study, all benign nodules detected on T2-weighted images were hypointense; moreover, all benign nodules displayed hypervascularity, whereas a single hypovascular hepatocellular carcinoma revealed hypointensity on T2-weighted images. We theorize that hypervascular nodules that present as hypointense on T2-weighted images may suggest benignity. However, benign hepatic nodules in Budd-Chiari syndrome do not always reveal hypointensity on T2-weighted images [2, 6]. In addition, we think that hepatocellular carcinomas arising in patients with Budd-Chiari syndrome could show hypointensity on T2-weighted images when the surrounding liver parenchyma has undergone severe congestion. Therefore, we believe that this finding does not necessarily exclude the possibility of malignancy.
A central scar may develop in a variety of large primary liver tumors, including focal nodular hyperplasia, giant hemangioma, and hepatocellular carcinoma [22]. For small hepatocellular carcinomas, however, a single instance among 103 tumors revealed a central scar in our study, whereas a central scar was found in six of 15 benign nodules larger than 1 cm in diameter on radiologic study. We believe that a hepatic nodule displaying a central scar can be diagnosed as benign with reasonable confidence in patients presenting with Budd-Chiari syndrome.
In conclusion, benign hepatic nodules are frequently observed in patients with Budd-Chiari syndrome. These nodules are typically small, multiple, and hypervascular. On MR imaging, the lesions often reveal hyperintensity on T1-weighed images and hypointensity on T2-weighted images. Pathologically, they often resemble focal nodular hyperplasia; moreover, the presence of a central scar is a characteristic feature of nodules greater than 1 cm in diameter. The pathogenesis of the nodules remains to be determined; however, the decrease in portal venous flow may be one of the possible factors.
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